The augmentation or replacement of soft tissue and non-load bearing bone such as skin, cartilage and tendon is typically done with implants which comprise an elastomer shell filled with a biocompatible material. See, e.g., U.S. Pat. Nos. 4,731,081; 4,772,284, 4,787,905, 4,995,885, 5,287,857, 5,219,360, and 5,658,329. A variety of problems are associated with implants such as these, including inflammation of surrounding tissue caused by frictional irritation, and rupture of the shell.
Hydrogels offer a potential solution to these problems. Hydrogels are polymeric materials that swell in water and retain a significant fraction of water within their structures without dissolving. Because the high water content of hydrogels is analogous to that of tissue, hydrogels are potentially more biocompatible than materials such as silicone. See, e.g., Hoffman, A. S., et al., Ann. New York Acad. Sci. 283:372-382 (1977); and Andrade, J. D., et al., Trans. Am. Soc. Artif. Intern. Organs 19:1 (1973).
The usefulness of hydrogels was originally limited by their lack of mechanical strength. It was quickly found, however, that this can be improved by crosslinking the polymers within a hydrogel. For example, the strength and hardness of a poly(vinyl alcohol) (PVA) hydrogel is dramatically improved when chemically crosslinked with an aldehyde such as formaldehyde, glutaraldehyde, terephthalaldehyde, and hexamethylenediamine. See, e.g., Singh, H., et al., J. Sci, Ind. Res. 39:162 (1980).
Another benefit of chemical crosslinking is that it allows the manufacture of porous hydrogels. For example, dopants such as sugars and salts can be added to the polymer solution from which a hydrogel is made. As the hydrogel is crosslinked, covalent bonds form around dopant molecules which, upon completion of the crosslinking, can be removed to provide a porous structure. This method allows precise control over pore size and pore density. Variables such as these affect macroscopic properties of hydrogels such as density and strength. See, e.g., U.S. Pat. Nos. 3,276,996; 3,663,470; and 4,083,906. More important, implants made of hydrogels which contain sufficient numbers of pores of suitable size can allow the ingrowth of tissue. This is desirable because tissue ingrowth ensures that an implant will remain rooted at the position where it was planted, and will not move over time.
The advantages of mechanical strength and porosity offered by chemical crosslinking are clear. Unfortunately, chemically crosslinked hydrogels contain crosslinking agents and byproducts that can render them unsuitable for implantation. Even careful washing of a chemically crosslinked hydrogel leaves residues that can leach into surrounding tissue. Hoffman, A. S., et al., Ann. New York Acad. Sci. 283:372-382 (1977). A further problem exhibited by chemically crosslinked hydrogels is their eventual calcification after long-term (e.g., ten to twenty years) implantation. See, e.g., Koutsopoulos, S., et al., J. Mater. Sci. Mater. Med. 9:421-424 (1998). This calcification, which results from the precipitation of calcium from bodily fluids, is believed to be due in part to the inability of bodily fluids to easily flow through covalently (e.g., chemically) crosslinked hydrogels.
In view of the problems associated with chemically crosslinked hydrogels, other methods of strengthening hydrogels have been investigated. A particularly promising method is freeze-thaw crosslinking. Over the past decade, researchers have discovered that hydrogels made of materials such as PVA and hyaluronic acid can be strengthened by their repeated freezing and thawing. See, e.g., Lazzeri, L., et al., J. Mat. Sci. Mat. Mel. 5:852-867 (1.994). This process induces a reorganization of the polymeric components of a hydrogel, and can lead to the formation of crystalline or quasi-crystalline regions within it. The molecular reorganization is believed to facilitate formation of intermolecular interactions such as hydrogen bonding. On a macroscopic scale, these interactions can dramatically increase the mechanical strength of a hydrogel. See, e.g., Nagura, M., et al., Polymer 30:762-765 (1989); Watase, M. and Nishinari, K., Makromol. Chem. 189:871-880 (1988); and Yamaura, K., et al., J. App. Polymer Sci. 37:2709-2718 (1989). In short, the freeze-thaw process is believed to induce a type of crosslinking, referred to as "physical crosslinking," that is characterized not by the formation of covalent bonds, but by the formation of stabilizing intermolecular interactions.
Unfortunately, the lack of covalent crosslinking in physically crosslinked hydrogels gives rise to problems that have not, until now, been solved. For example, hydrogel materials such as PVA are sold as mixtures of polymers with average molecular weights and particular molecular weight distributions. These mixtures typically comprise low molecular weight polymers (e.g., polymers having molecular weights of less than about 10,000 g/mol) that might leach out after long-term hydration. When hydrogels are made from such PVA mixtures using chemical crosslinking methods, however, each polymer molecule is covalently linked to the whole, or to a substantial part of the whole. The result is a hydrogel that contains no unbound low molecular weight molecules. But chemically unaltered, low molecular weight molecules remain in physically crosslinked hydrogels. Thus, an implanted freeze-thaw hydrogel can potentially bleed low molecular weight molecules into surrounding tissues over time.
Another drawback of physical (e.g., freeze-thaw) crosslinking is that its effectiveness in strengthening a hydrogel depends upon the ordered arrangement of the polymers that form the hydrogel, whereas covalent crosslinking does not. Thus the strength of a freeze-thaw hydrogel can be highly dependent on its porosity (i.e., average pore size and pore density). This relationship between strength and porosity is reflected in the freeze-thaw process itself, wherein each freeze-thaw cycle induces a reorganization of the polymers within a hydrogel that reduces the number and size of randomly, naturally occurring pores and provides a more densely packed (and accordingly stronger) structure.
Because of the freeze-thaw process affects both strength and porosity, the latter is typically sacrificed for the former. For example, U.S. Pat. No. 4,734,097 discloses a method of making a PVA hydrogel that is allegedly strong enough to be used as an implant. When implanted, however, the hydrogel does not allow tissue ingrowth. Similarly, U.S. Pat. No. 4,808,353 and WO 98/50017 each disclose allegedly improved freeze-thaw processes, but neither provides a method of producing a hydrogel that is both strong and porous. Further, methods such as these, wherein the strength and porosity of a hydrogel are both controlled by the number of freeze-thaw cycles, can yield hydrogels comprised of unevenly distributed pores of widely varying sizes, many of which are too small or too large to be useful and serve only to weaken the hydrogel. This is because adjustment of factors such as the number of freeze-thaw cycles or the freeze or thaw temperatures provides little control over the average pore size and pore density.
For the above reasons, a method is desired which allows manufacture of a hydrogel which combines the benefits of conventional (i.e., prior) physically and chemically crosslinked hydrogels.